Alzheimer's disease (AD) is a highly age-related, progressive central nervous system degenerative disease. Its early clinical manifestations are memory and cognition, executive dysfunction such as recent memory loss, aphasia, apraxia, agnosia, etc. and abnormal personality changes etc.; mid-term clinical manifestations are personality and behavior changes such as irritability, panic, sleep disorder, hallucination and the like; and late clinical manifestations are lack of logical thinking, bedridden, incompetence of taking care of oneself and the like.
Statistics show that there are currently about 30 million AD patients worldwide, and with the aging of the world's population, the number of AD patients worldwide will exceed 100 million by the year of 2050. AD patients will not be able to live independently in the middle and late stages, and need to be taken care of by medical staff. According to statistics, the US currently spends more than 300 billion dollars annually on AD care (US, Alzheimer's Disease Association). According to the latest statistics released by China's National Bureau of Statistics, by the end of 2014, the number of the elderly aged 60 and above in China had reached 212.42 million, accounting for 15.5% of the total population, and the population aged 65 and above was 137.55 million, accounting for 10.1% of the total population. At present, the number of AD patients in China has exceeded 8 million. With the aging of the population in China, the number of AD patients will increase dramatically. It is estimated that by 2050, the number of AD patients in China will reach nearly 30 million, and AD thus has become a significant burden on society and families of China.
AD patients have two important histopathological features: in the brain tissues associated with learning and memory such as cerebral cortex, hippocampus, forebrain basal ganglia and thalamus, there are a large number of senile plaques (SP) formed by the aggregation of Aβ, and neurofibrillary tangles resulted from hyperphosphorylation of Tau proteins. Studies show that when Aβ increases in the brain of AD patients, Aβ protein aggregates to form highly neurotoxic oligomers, resulting in changes of oxidative stress, inflammation and hyperphosphorylation of Tau proteins in the brain, and inducing neuronal death ultimately. Therefore, Aβ, as an initiation factor in the pathological changes of AD, plays a crucial role in the pathological process of AD patients.
Aβ, no matter in the brains of familial AD patients or non-familial scattered AD patients, has increased significantly before the onset of AD symptoms, indicating that Aβ is an initiation factor that leads to pathological changes of AD. In addition, it is also found in the AD model mice with high expression of Aβ that the increase of Aβ is earlier than the appearance of memory impairment; meanwhile, when BACE1 (the rate-limiting enzyme in the production of Aβ) is knocked out in the AD model mice, memory impairment and neuronal apoptosis are significantly reversed with notable decease of Aβ. As such, Aβ has become an important target for new anti-AD therapeutics, and AD model mice with high expression of Aβ have also become a well-accepted model for evaluating the efficacy of such anti-AD therapeutics. APP/PS1 double transgenic AD model mice (B6C3 transgenic mice, APPswe, PS1dE9) have high expression of chimeric mouse/human Swedish mutation APP (Mo/HuAPP695swe) and presenilin-1 that is humanized with the deletion of the 9th exon (PS1-dE9). Both of the two gene mutations are recognized as the main pathogenic mutations in familial AD. Such APP/PS1 transgenic AD model mice begin to develop Aβ deposits at about 6 months, and memory impairment occurs at about 7 months. As such, APP/PS1 transgenic mice become model mice suitable for the efficacy evaluation in the development of anti-AD therapeutics.
Memantine is currently used in clinic for the treatment of AD. However, memantine can only ameliorate the symptoms of AD without blocking its pathological progression (Areosa S A et al., Memantine for dementia. (2005) Cochrane Database Syst Rev. (3): CD003154). It is urgently needed to develop a drug which can ameliorate the symptoms of AD while blocking its pathological progression.
It is reported in Chinese patent application No. CN 103467417 A that arctigenin has the effect of inhibiting the production of Aβ by activating phosphorylation of AMPK and reducing the phosphorylation of AKT, inhibiting the mTOR pathway which results in increased autophagy, thereby increasing the clearance of Aβ, and thus has a therapeutic effect on AD. However, according to further investigations of the present inventors, arctigenin has poor oral bioavailability, and thus cannot be used for oral administration. Developing arctigenin derivatives with improved oral bioavailability would benefit in improving patient compliance.